I. Introduction

These conditions comprise a very large number of genetic biochemical/
physiological entities, most of which are academic curiosities whose
major effect on medicine is to add to the surfeit of useless scientific
information. However, several of these conditions (e.g., sickle cell
anemia, hemoglobin SC disease, and some thalassemias) are common major
life-threatening diseases, and some others (e.g., most
thalassemias, hemoglobin E disease, and hemoglobin O disease) are
conditions that produce clinically noticeable -- if not serious --
effects and can cause the unaware physician a lot of frustration and
the hapless patient a lot of expense and inconvenience. We will study a
few hemoglobinopathies and thalassemias of special importance. It
should be kept in mind, though, that there are literally hundreds of
diseases in these categories.

II. Definitions

Hemoglobinopathy: A genetic defect that results in
abnormal structure of one of the globin chains of the hemoglobin
molecule. Although the suffix "-pathy" would conjure an image of
"disease," most of the hemoglobinopathies are not clinically apparent.
Others produce asymptomatic abnormal hematologic laboratory findings. A
very few produce serious disease. The genetic defect may be due to
substitution of one amino acid for another (as with the very common Hb
S and Hb C and the great majority of the other abnormal hemoglobins),
deletion of a portion of the amino acid sequence (Hb Gun Hill),
abnormal hybridization between two chains (Hb Lepore), or abnormal
elongation of the globin chain (Hb Constant Spring). The abnormal chain
that results may be the chain (Hb GPhiladelphia),
chain (Hb S,
Hb C), chain (Hb FTexas), or chain (Hb
A2Flatbush). These abnormal hemoglobins can have a
variety of physiologically significant effects, discussed below in
greater depth, but the most severe hemoglobinopathies (Hb S and Hb C
diseases) are characterized by hemolysis.

Thalassemia: A genetic defect that results in
production of an abnormally low quantity of a given hemoglobin chain or
chains. The defect may affect the , , , or chain, or may affect some combination of the , ,
and chain
in the same patient (but never the and chain together). The result is an imbalance in
production of globin chains and the production of an inadequate number
of red cells. The cells which are produced are hypochromic/microcytic
and contain a surfeit of the unaffected chains which cannot
stoichiometrically "mate" with the inadequate supply of thalassemic
chains. These "bachelor" chains can produce adverse effects on the red
cell and lead to destruction of the red cell in the marrow (ineffective
erythropoiesis) and in the circulation (hemolysis). Note that these two
definitions are not mutually exclusive -- some hemoglobinopathies may
also be thalassemias, in that a structurally abnormal hemoglobin
(hemoglobinopathy) may also be underproduced (thalassemia). Some, but
not all, hemoglobinopathies and thalassemias are hemolytic anemias.
These nosologic concepts are summarized by the Venn diagram below.

III. Pathophysiology of hemoglobinopathies

Messing around with the amino acid sequence of a globin chain has
something of a red kryptonite effect. While some positions on the
protein chain can tolerate a lot of substitutions without compromising
the physiologic integrity of hemoglobin, other positions are very
sensitive to amino acid substitutions. For instance, substitution of
valine or lysine for glutamate at position 6 of the chain produces
hemoglobins S and C, respectively, which form intraerythrocytic
tactoids (see below) and crystals (again respectively) that cause
premature destruction of the rbc (hemolysis). On the other hand,
substitution of glutamate, asparagine, and threonine for lysine at
position 59 of the chain produces, respectively, hemoglobins IHigh Wycombe, JLome, and JKaoshiung, all of which are physiologically
indistinguishable from normal Hb A. Without venturing too deeply into
tedious stereochemistry, we can say that abnormal globin structure can
functionally manifest itself in one or more of the following ways:

Increased O2
affinity

These hemoglobins tend to result when mutations affect the portions
of the amino acid sequence that compose 1) the regions of contact
between and
chains, 2)
the C-terminal regions, and 3) the regions that form the pocket which
binds 2,3-DPG. The hemoglobin eagerly scarfs up the O2 from the alveoli but then only stingily
gives it up to the peripheral tissues. The kidney, always compulsively
vigilant for hypoxia, cranks out the erythropoietin thinking that a few
extra red cells might help out matters. Erythropoiesis then is
stimulated, even though there is no anemia, and erythrocytosis
(increased total body rbc mass, increased blood hemoglobin
concentration, increased hematocrit) is the result.

It is important to know that these rare increased O2 affinity hemoglobins exist to prevent
diagnostic errors from occurring in working up patients presenting with
erythrocytosis (which is much more commonly caused by other conditions,
including polycythemia vera [a neoplasm], cigarette smoking,
psychosocial stress, chronic residence at high altitudes, and chronic
lung disease). Examples of these include Hb Chesapeake and Hb
JCapetown.

Decreased O2
affinity

This is the other side of the coin. These hemoglobins are reluctant
to pick up O2 from the lung. The result
is a decreased proportion of hemoglobin that is oxygenated at a given
PO2. The remainder of the hemoglobin is,
of course, deoxygenated and is blue. If the level of blue hemoglobin
exceeds 5 g/dL in capillary blood, the clinical result is cyanosis, a
bluish discoloration of skin and mucous membranes.

Again, it is important to know about these hemoglobins and keep them
in the back of your mind when working up cases of cyanosis, a condition
much more commonly caused by pulmonary dysfunction or right-to-left
cardiovascular shunts. Examples of low O2 affinity hemoglobins include Hb Seattle, Hb
Vancouver, and Hb Mobile.

Methemoglobinemia

These hemoglobins are a special class of low O2 affinity hemoglobin variants that are
characterized by the presence of heme that contains iron in the ferric
(Fe+++) oxidation state, rather than the
normal ferrous (Fe++) state. These
methemoglobins are all designated "Hb M" and further divided
by the geographic site of their discovery, e.g., Hb MSaskatoon and Hb MKankakee. The affected patients have
cyanosis, since the methemoglobin is useless in O2 binding.

Methemoglobinemia due to hemoglobinopathy should be distinguished
from methemoglobinemia due to other causes, such as
NADH-diaphorase deficiency. This enzyme is needed for
the reduction (to heme) of metheme that accumulates as a result of
normal metabolic processes. Congenital absence of NADH-diaphorase
causes an accumulation of metheme, despite the fact that the structure
of the globin chain is normal. Toxic methemoglobinemia
occurs in normal individuals exposed to certain oxidizing drugs and
other compounds in the environment, even though these individuals have
normal hemoglobin structure and a normal complement of NADH-diaphorase.
In such victims, the oxidizing power of the toxin overwhelms the normal
antioxidant defenses.

Since methemoglobin is a brown pigment, patients with clinically
severe methemoglobinemia have obviously brown blood. This
observation allows one to make a clever and memorable diagnosis at the
bedside during the patient's first venipuncture.

Unstable hemoglobin (Heinz body anemia)

Certain abnormalities in the globin chain sequence produce a
hemoglobin that is intrinsically unstable. When the hemoglobin
destabilizes, it forms up into erythrocyte inclusions called Heinz
bodies. It is important to know that Heinz bodies are not visible
in cells stained with the routine Wright stain. It is necessary
for the cells to be stained with a supravital dye (such as brilliant
cresyl blue, which can also be used to demonstrate reticulocytes) to be
visible. These inclusions attach to the internal aspect of the rbc
membrane and reduce the deformability of the cell and basically turn it
into spleenfodder. The result is hemolytic anemia. All of these
hemoglobins are rare; inheritance is autosomal dominant. Homozygotes
have not been described. Examples of unstable hemoglobins are Hb Gun
Hill, Hb Leiden, and Hb Köln.

Sickling and crystallization

These phenomena occur respectively in Hb S and Hb C, the most
important of the abnormal hemoglobins. We will deal with these in
greater depth next.

IV. Specific hemoglobinopathies

A. Hemoglobin S and sickle cell disease

1. Epidemiology and genetics

The Hb S gene is found primarily in populations of native tropical
African origin (which include most African-Americans). The incidence of
the gene in some African populations is as high as 40%; in
African-Americans the incidence is 8%. The gene is also found with less
frequency in non-Indo-European aboriginal peoples of India and in the
Middle East. Rare cases have been reported in Caucasians of
Mediterranean descent. The gene established itself in the tropical
African population presumably because its expression in heterozygotes
(sickle cell trait) affords some protection against
the clinical consequences of Plasmodium falciparum infestation.
Unfortunately, homozygous expression produces sickle cell
disease, which is a chronic hemolytic anemia and
vaso-occlusive condition that usually takes the life of the patient.

Hemoglobin S has the peculiar characteristic of expressing its
biochemical instability by precipitating out of solution and forming up
into long microtubular arrays called tactoids. The
erythrocytes which contain the Hb S stretch around the tactoids to form
the characteristic long, pointed, slightly curved cells called (with
somewhat liberal imagination) "sickle cells." Only the deoxygenated
form of Hb S (deoxy-Hb S) makes tactoids. The greater the proportion
of Hb S in the cell, the greater is the propensity to sickle.
Therefore, persons with 100% Hb S (being homozygotes) sickle under
everyday conditions, while typical heterozygotes (who usually have
about 30-40% Hb S) do not sickle except possibly under extraordinary
physiologic conditions. Since Hb S is a chain mutation, the disease does not
manifest itself until six months of age; prior to that time the Hb S is
sufficiently "watered down" by Hb F (22), which of course has no chain.

In post-infancy individuals homozygous for the Hb S gene, 97+% of the
hemoglobin is Hb S, the remainder being the normal minor hemoglobin, Hb
A2 (22). Several coexisting genetic
"abnormalities" (actually godsends) prevalent in African populaitons
may ameliorate the course of the disease:

-thalassemia carriers (which comprise 20% of
African-Americans!) have a lower MCHC than normal individuals. It has
been suggested that a low MCHC is beneficial in decreasing the
vaso-occlusive properties of sickled cells. These sickle cell patients
live longer and have a milder disease than do non-thalassemic patients.
Thalassemia is discussed in greater detail below.

Hereditary persistence of fetal hemoglobin
(HPFH) has established itself in the black population and allows Hb F
to so dilute the Hb S that sickling does not occur or is less
prominent. In these people the Hb F gene does not "turn off" in infancy
but persists indefinitely.

G-6-PD deficiency has been suggested as an
ameliorative condition for sickle cell disease. This is controversial;
the pathophysiologic basis of any such effect must be pretty obscure.

2. Clinical findings

Sickle cell anemia is a particularly bad disease in that not only is it
a hemolytic anemia, but also a vaso-occlusive condition. The clinical
findings can then be divided into one of these two groups:

a. Effects of chronic hemolysis

Anemia. Pretty much self-explanatory

Jaundice, due to rapid heme turnover and
subsequent generation of bilirubin

Cholelithiasis. It has been classically taught
that sickle cell patients are prone to the formation of calcium
bilirubinate gallstones due to excess bilirubin secretion into the
hepatobiliary tree.

Aplastic crisis. Many of us have brief episodes of
marrow aplasia as a result of common viral infections. With a normal
erythrocyte life span of 120 days, no anemia results from an unnoticed
marrow shut-down of a few days. However, the sickle cell patients, with
their markedly abbreviated rbc life span, can have a precipitous fall
in hematocrit (and retic count) under such conditions. This may be
life-threatening.

Hemolytic crisis. Most sickle cell patients
establish a stable, tonic level of hemolysis. Rarely, for obscure
reasons, they experience a catastrophic fall in hematocrit, increasing
intensity of jaundice, and increasing reticulocyte count. This is
called a "hemolytic crisis."

b. Effects of vaso-occlusion

Dactylitis. Resulting presumably from infarction
or ischemia of the bones of the hands and feet, this is often the
presenting manifestation of sickle cell disease in a six-months-old
infant. The hands and feet are swollen and painful.

Autosplenectomy. In childhood, the spleen is
enlarged due to excess activity in destruction of the sickled
erythrocytes. Gradually, the spleen infarcts itself down to a fibrous
nubbin.

Priapism. This refers to a painful and sustained
penile erection, apparently due to sludging of sickled cells in the
corpora cavernosa. Sometimes the penis has to be surgically
decompressed. Repeated episodes of priapism cause the spongy erectile
tissues to be replaced by fibrous tissue, with impotence being the end
result.

Renal papillary necrosis. The physiologic function
of the loops of Henle make the renal medulla an eldritch, unbodylike
area of high hematocrit, high osmolarity, low pH, hemodynamic stasis,
and low PO2. All of these
conditions predispose to sickling and infarctive loss of the papillae
of the pyramids. The result is inability to concentrate and dilute
urine. Even sickle cell trait individuals may experience
episodes of hematuria, presumably due to this mechanism.

Infarctive (painful) crisis. Increased sickling
activity may be brought about by any general stress on the body,
especially infection. Almost any organ may suffer acute infarction
(includinmg the heart), and pain is the chief symptom.

Sequestration crisis. This occurs mostly in
infants and young children and is characterized by sudden pooling of
sickled erythrocytes in the RES and vascular compartment. This produces
a sudden fall in hematocrit. Sequestration crisis may be the most
common cause of death in sickle cell patients in the youngest age
group.

Leg ulcers. After all of the disasters mentioned
above, this seems trivial. However, the deep, nonhealing ulcers of skin
and tela subcutanea (classically around the medial malleolus) may be
the only clinical manifestation of sickle cell disease in an otherwise
well-compensated patient. These may be the only bugaboo standing
between the patient and a productive, financially solvent life.

B. Hemoglobin C

The gene for Hb C is also prevalent in the African-American population
but with less frequency (2-3%) than that of the sickle cell gene. Hb C
does not form tactoids, but intracellular blunt ended
crystalloids. The result is decreased rbc survival
time; however, hemolysis is not as severe as in sickle cell disease,
and the vaso-occlusive phenomena, so devastating in sickle cell
disease, are not generally noted. Like sickle cell trait, the Hb C
trait is asymptomatic. Homozygotes (and some heterozygotes) for Hb C
often have many target cells (codocytes) in the peripheral smear, but
the crystals, although pathognomonic, are only occasionally seen. The
prognosis of homozygous Hb C disease is excellent.

An individual may inherit a Hb S gene from one parent and a Hb C gene
from the other. The result of this double whammy is Hb SC
disease. The clinical severity of this condition is
intermediate between that of sickle cell disease and Hb C disease,
except that visual damage due to retinal vascular lesions is
characteristically worse in SC disease than in sickle cell anemia.
The intracellular bodies that occur upon hemoglobin destabilization in
SC disease are curious hybrids of the blunt-ended crystalloids of Hb C
and the sharp-pointed tactoids of Hb S, in that they often have one
pointed end and one blunt end, thus vaguely resembling arrowheads.

C. Hemoglobin E

This is a very common chain mutation among Southeast Asians. The Thai and Khmer
groups have the highest frequency, followed by Burmese and Malays, then
Vietnamese and Bengalis. The gene does not occur in ethnic Han
Chinese or Japanese. The heterozygous state is asymptomatic but causes
microcytosis without anemia, thus resembling some cases of thalassemia minor
(see below). The homozygous state has more severe microcytosis and
hypochromia, but little, if any, anemia (this is also reminiscent of
thalassemia minor). Hemoglobin E should always be considered working up
an unexplained microcytosis in a member of one of the affected ethnic
groups.

V. Thalassemia

A. Genetics

Understanding the thalassemias can be facilitated by reviewing the
genesis of the normal post-embryonal hemoglobins:

Chromosome 16 contains the genes for the all-important chain. The genes
for all of the other important globin chains are on chromosome 11,
where they are closely linked. The linkage means (if you will briefly
abuse yourself by recalling basic genetics) that the genes tend to be
inherited as a group, as opposed to non-linked (or distantly linked)
genes which assort independently due to crossing over during
gametogenesis. Because of the linkage, a mutation that affects the rate
of production of the chain not uncommonly affects rate of production of the
adjacent
chain. An individual carrying such a mutation would then have a gene
for " thalassemia." He
or she could pass on the
thalassemia gene to offspring but would essentially never, say, pass a
thalassemia
gene to one child and a thalassemia gene to another. Conversely, since the genome
for the
chain is on a completely different chromosome than the genes for all
the other chains, one would expect no mutation in a chromosome 11 chain
gene (,,) to
affect
chain production. Moreover, if some poor shlimazel happened to inherit
an
thalassemia gene from one parent and a thalassemia gene from another, he would
not tend to pass both abnormal genes on as a unit to his or her
offspring. One kid (out of a representative Mendelian sibship of four)
would get the abnormal gene, one would get the abnormal , one would get
neither, and one would get both.

B. Biochemistry and pathophysiology

But enough of Mendel! We're in med school to learn about hemoglobin,
right? Whatever the genetics, the clinical problem in the thalassemias
is the inability to maintain a balance between the synthesis rate of
one type of globin chain vis-à-vis that of its mate. Even though
thalassemias have been described for all four of the above chains, we
will consider only those that involve the chain (the thalassemias and thalassemias) and
the chain
(
thalassemias). It will be useful to review what kind of hemoglobins you
can build by mixing and matching globin chains:

Hemo-globin

Globin chain composition

Notes

A

22

The only physiologically important adult hemoglobin in normal
individuals. Includes the post-translational glycosylated hemoglobins
A1a, A1b, and A1c, the last being important in monitoring
diabetics.

F

22

The major physiologic hemoglobin in post embryonal fetuses. Adapted
best for lowered intrauterine O2 tension
because of its left-shifted Hb-O2
dissociation curve (allowing O2 to be
more readily picked up from maternal circulation). Production normally
turns off in early infancy. Proportion of circulating Hb F fades to
insignificance at about 6 months of age.

A2

22

Medical philosopher's proof of the existence of God (and God's love
of physicians). Apparently put here solely as a marker for doctors
trying to figure out whether a patient has iron deficiency anemia or
thalassemia.
Normally less than 3% of circulating hemoglobin (thus physiologically
insignificant), Hb A2is slightly
elevated in most thalassemias, but normal or decreased in iron deficiency,
thus making it a nifty marker for evaluating microcytic, hypochromic
anemias.

Gower 1
Gower 2
Portland

222222

Very early normal embryonal hemoglobins that disappear after 8
weeks of gestation. The only one of clinical importance is Hb Portland,
which may be seen at birth in cases of the severest form of
thalassemia.

H

4

Abnormal hemoglobin produced in cases of thalassemia,
when excess
chains decide to get it on with each other, there not being enough chains to go
around. Intrinsically unstable, Hb H produces Heinz bodies in the
erythrocytes and subsequent hemolysis.

Bart's

4

Delinquent youth gang analogue of Hb H. This abnormal hemoglobin is
found in infants with thalassemia. Detecting presence of Hb Bart's in
cord blood may be the only practical way to screen for the very large
number of individuals who are silent carriers of one type of thalassemia (see
below).

C. Beta thalassemia

Although this is the classic form of thalassemia it is not the most
common. The first description was written by Dr. Thomas Cooley in 1925.
The term "Cooley's anemia" has been used synonymously with clinically
severe forms of thalassemia, although the remainder of Cooley's career was
so undistinguished as to cause some to suggest that his name is not
worthy of eponymous immortality. Cooley's anemia was a fatal microcytic
anemia of children of Mediterranean descent. The name "thalassemia" was
coined to reflect the original geographic home of the target population
( "thalassa" is the classical Greek name for the Mediterranean Sea).
Over the years, it became clear that many other groups (Africans,
African-Americans, Arabs, Indians, and Southeast Asians) are affected.
In fact, thalassemias in general tend to affect races of people that
hail from a tropical belt that girdles the Mediterranean and extends
all the way through the Indian subcontinent to Southeast Asia.

There are a multiplicity of different thalassemia genes that give rise to a
clinically heterogeneous spectrum ranging from asymptomatic expression
to classical, deadly Cooley's anemia. It is convenient to group the
various
thalassemias into two groups, based on the amount of globin chain
production:

0 thalassemia

This abnormal gene allows no production of chains.
Individuals homozygous for this gene produce only Hb A2, Hb F (and very little of that after six
months of age), and unstable 4
tetramers that trash the red cells while they are still in the
marrow. As you might imagine, these people are in pretty dire straits
unless some guardian angel has given them another, independent gene for
hereditary persistence of fetal hemoglobin (HPFH). This prevents the Hb
F spigot from turning down to a trickle at six months. Such persons can
live to ripe old age and still be young at heart.

+ thalassemia

This abnormal gene allows some, but still subnormal, production of
chains.
People homozygous for this gene will make a subnormal amount of Hb A
but will still have trouble with the destructive effects of 4 tetramers on the erythrocytes and
erythrocyte precursors in the marrow. The + genes can
be further subdivided into the classic + (severe) form, seen in
Mediterranean Caucasians, and the mild + (Negro) form seen in blacks.
Nowadays this gene has its highest population concentration in Liberia.

Although these genes are remarkably varied in their effect on chain synthesis
rate, one can make up some useful rules of thumb:

Individuals heterozygous for any of the thalassemia genes
are either silent carriers or have minimal clinical effects, usually
manifested as a borderline anemia (Hct ~ 35 cL/L)
with disproportionate microcytosis (MCV ~ 60 fL) and a
reciprocally high rbc count (~ 6 x 106/µL). The Hb A2 is increased. This clinical presentation is
called thalassemia minor. It makes for interesting
wine-tasting party conversation if you have this condition, and all
that your friends can muster is chronic fatigue syndrome. Your kids
should have no problems if you just marry a Teuton, Slav, Balt, or
Lapp.

Individuals homozygous for all of the thalassemia genes
[except the + (Negro) gene] have severe
anemia and some or all of the pathophysiological consequences given in
the diagram below. This is classic Cooley's anemia and is termed
thalassemia major. This is bad news.

Individuals homozygous for the + (Negro)
gene and several other miscellaneous types of mildly behaving genes
have a relatively mild clinical anemia called thalassemia
intermedia. These patients may require transfusion, but only
later in life than is the case in the very sick children with
thalassemia major.

The pathophysiology of thalassemia major is best understood by going and
getting yourself a beer (or politically correct beverage), watching a
little TV, doing one or two other chores to postpone the inevitable,
and then sitting down to study the next diagram.

While studying the illustration, consider the following observations
concerning
thalassemia:

Since there is a decrease in the synthesis of chains, there is
a net decreased synthesis of Hb A. With less Hb A available to fill the
red cells, the result is microcytic anemia. Whereas in
iron deficiency microcytosis occurs because there is not enough
heme, in thalassemia the same thing occurs because there is
not enough globin.

Since the body cannot make enough chains, it makes a feeble attempt to
compensate by trying to churn out chains. The result is increased Hb A2, which can be measured easily and
inexpensively by column chromatography. This is a pretty specific test
for the diagnosis of thalassemia. Pitfall: both and chains are decreased in thalassemia, which is not rare and presents like thalassemia,
except that the Hb A2 is not
elevated. You would expect this since Hb A2 contains chains).

In some cases of thalassemia, there is attempt at compensation by
maintaining some production of Hb F. This has some
pathophysiologic consequences (as shown above) and also provides a
laboratory marker to assist in diagnosis. Retention of Hb F production
is not as common as increased rbc Hb A2
content.

In severe forms of thalassemia, the anemia due to failure to
make adequate amounts of Hb A is compounded by the hemolysis,
ineffective erythropoiesis, and extramedullary hematopoiesis brought on
by precipitation of 4 tetramers (which are
unstable). In classic Cooley's anemia, the ineffective erythropoiesis
dominates the clinical picture by producing tremendous expansion of the
marrow space, manifested by the so-called "tower skull" with an x-ray
showing innumerable vertical bony striae between the inner and outer
tables of the calvarium. This radiographic feature is fancifully called
the "hair-on-end appearance" by radiologists, and the
"guy-who-accidentally-sat-on-a-Van-de-Graaff-generator appearance" by
those wacky electrical engineers. Extramedullary hematopoiesis and
hemolysis causes splenomegaly, which produces
hypersplenism, and more hemolysis.

The high turnover state caused by the tremendous
erythroproliferative activity causes wastage of folate and may produce
a complicating megaloblastic anemia. Another effect of
the high turnover state is hyperuricemia (due to
catabolism of the purine content of cellular DNA).

Classically in thalassemia major, the treatment is the cause of
death. The children are maintained by transfusions until about age ten
years, at which time they start to show symptoms of excess iron
loading. This happens because the transfusion bypasses the body's
normal gastrointestinal mechanism of iron intake and excretion. The
iron is poured into the bloodstream directly; the body cannot excrete
it fast enough. First iron (as hemosiderin) fills the cytoplasm of the
RES phagocytes and then starts to be deposited in the parenchymal cells
of just about every organ of the body. The pancreas, liver, myocardium,
adrenals, and gonads are among the organs most sensitive to iron
toxicity. The clincial result is diabetes mellitus, hepatic
cirrhosis, congestive heart failure, adrenal insufficiency,
and failure to undergo puberty. Death used to occur in
the second or third decade of life, the most common immediate cause
being complications of heart failure. Nowadays, thal major patients
live longer because of advances in chelation therapy. To achieve such
longevity, they must submit to daily subcutaneous injections of the
parenteral chelating agent, deferoxamine. These injections are given by
pump, usually overnight, and last 9 to 12 hours each. An oral chelating
drug in presently under development in Europe.

D. Alpha thalassemia

The
thalassemias include the most common of all hemoglobinopathies and
thalassemias. One form of thalassemia is very common in African-Americans.
Fortunately this form is so mild that its very detection is almost
impossible in adult heterozygotes, and even homozygotes are
asymptomatic with mild laboratory abnormalities. Yet another form of
thalassemia, fortunately uncommon, produces the most severe disease of
all the hemoglobinopathies and thalassemias and usually takes the life
of its victim even before birth. Surely thalassemia is a disease of extremes!

It is helpful to consider two concepts concerning thalassemia:

Unlike
thalassemia, thalassemia is present even before birth, since the chain is
integral to all hemoglobins past the very primordial Hb Gower 1 and Hb
Portland. Thus, individuals, born and unborn, who carry one of these
genes underproduce Hb Gower 2, Hb F, Hb A, and Hb A2. Obviously then, elevated Hb A2 cannot be used as a diagnostic marker for
thalassemia.

As noted in an illustration above, each individual has four
genes for the globin chain, which can be denoted as /. Each haplotype
() is inherited
from a parent as an indestructible, non-crossoverable pair. In thalassemias,
anywhere from one to all four of these genes of the diplotype (/) can be deleted
(or transformed into some "bad guy" gene that doesn't do anything),
producing a dose-related depression of chain synthesis. Thus, the (-/) diplotype
produces the mildest condition, while (--/--) produces the fatal
intrauterine disease. The (-) gene is called the " thalassemia-2"
gene while the (--) gene is termed the " thalassemia-1" gene. One can be
homozygous or heterozygous for each of these, to give four possible
diplotypes (-/, -/-, --/, --/--). An additional diplotype is the double
heterozygote for thalassemia-1 and thalassemia-2 (-/--). Since the thalassemia-1
and
thalassemia-2 genes tend to occur in different races (Asians and
Africans, respectively, between which there is a low rate of
intermarriage), this combination is not common. Let us look at the
various nefarious gene combinations individually:

In the above diagram, the normal diplotype is compared with the
heterozygous state for thalassemia-2. The latter occurs in 20% of all
African-Americans. It produces no symptoms and no abnormalities on
routine laboratory tests. The only practical way to detect it is to
screen all black infants at birth for Hb Bart's (4), and even this technique
will miss some individuals. It is thought that the reason for the high
prevalence of this gene in the black population is that it may be an
"anti-sickle cell" gene. It turns out that Hb S homozygotes have a
milder course of sickle cell anemia if they also are silent carriers
for
thalassemia.

The the two diplotypes given above, two of the four genes are
trashed by "bad guy" mutations. Such individuals are usually not anemic
but may have microcytosis. They become victims of the medical system
when they are subjected to expensive and time consuming testing in a
quixotic search for some serious hematologic condition that does not
exist. About the only way to make a diagnosis of one of these
conditions is to eliminate other causes of microcytosis and/or check
rbc indices on all available blood (no pun intended) relatives. Amidst
all this shenanigans lurks a somber note -- if an thalassemia-1
heterozygote finds his or her true love in another thalassemia-1
heterozygote, one-fourth of the issue of such a union will suffer the
always lethal homozygous state.

The double heterozygote on the left has "hemoglobin H
disease," so named because of the presence of a significant
proportion of the hemoglobin composed of four chains. Affected
infants will, of course, show some Hb Bart's as well. These people have
a hemolytic anemia which varies from very mild to that which clinically
resembles
thalassemia major.

The
thalassemia-1 homozygote, on the right, is allowed no
production of chains. The only hemoglobins present are Hb Bart's, Hb H,
and Hb Portland. Most of the affected die in utero or within
hours after birth. Autopsy shows massive extramedullary hematopoiesis
in virtually every parenchymatous organ of the body. The severe anemia
causes congestive heart failure and subsequent massive total body
edema, termed "hydrops fetalis." Parenthetically, it
should be noted that hydrops (from which springs the term "dropsy") is
not limited to thalassemia but is seen in any conditon that causes
severe heart failure in utero, such as in the anemia due to
alloimmune hemolytic disease of the newborn.